Expression of inducible nitric oxide synthase and interleukin-12 in experimental necrotizing enterocolitis

Evan P. Nadler, Eva Dickinson, Alex Knisely, Xiao Ru Zhang, Patricia Boyle, Donna Beer-Stolz, Simon C. Watkins, Henri R. Ford

Research output: Contribution to journalArticlepeer-review

192 Scopus citations


Background. Previous investigators have relied on administration of pro- inflammatory cytokines or invasive surgical procedures to reproduce the morphologic changes of necrotizing enterocolitis (NEC) in rats. However, these artificial insults do not mimic the human disease. We developed a reproducible model of NEC in rats that more closely resembles human NEC and determined the pattern of inflammatory cytokine expression in this model. Materials and methods. Newborn rats were randomized into four groups. Groups 1 and 2 were breast-fed, while Groups 3 and 4 were gavaged with formula thrice daily. In addition, Groups 2 and 4 were subjected to 3 min of hypoxia thrice daily, prior to each feeding. The rats were killed on day 4 and the distal 2 cm of terminal ileum was harvested for morphological studies and analysis of inflammatory cytokine mRNA expression. Results. Nearly 70% of formula-fed neonatal rats displayed moderate or severe morphological abnormalities resembling human NEC. Breast-fed pups had normal histology. The terminal ileum from rats with abnormal histology demonstrated increased inducible nitric oxide synthase (iNOS) expression, decreased interleukin-12 (IL-12) mRNA expression, and enterocyte apoptosis. There was a trend toward upregulation of IFN-γ mRNA, but no difference in expression of TNF-α mRNA. Hypoxia did not significantly alter intestinal morphology or mRNA expression. Conclusions. Formula-fed neonatal rats, with or without hypoxia, exhibit morphological changes in the intestinal epithelium similar to those seen in patients with acute NEC. The mechanism likely involves upregulation of iNOS mRNA, enterocyte apoptosis, and decreased IL-12 production in the intestinal epithelium. This model may offer a simple reproducible method for inducing experimental NEC. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)71-77
Number of pages7
JournalJournal of Surgical Research
Issue number1
StatePublished - Jul 2000
Externally publishedYes


  • Apoptosis
  • Gut barrier failure
  • Interferon-γ
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Surgery


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